DNA methylation at an enhancer of the three prime repair exonuclease 2 gene (TREX2) is linked to gene expression and survival in laryngeal cancer.

BACKGROUND: Genetic aberrations in DNA repair genes are linked to cancer, but less is reported about epigenetic regulation of DNA repair and functional consequences. We investigated the intragenic methylation loss at the three prime repair exonuclease 2 (TREX2) locus in laryngeal (n = 256) and colorectal cancer cases (n = 95) and in pan-cancer data from The Cancer Genome Atlas (TCGA). RESULTS: Significant methylation loss at an intragenic site of TREX2 was a frequent trait in both patient cohorts (p = 0.016 and < 0.001, respectively) and in 15 out of 22 TCGA studies. Methylation loss correlated with immunohistochemically staining for TREX2 (p < 0.0001) in laryngeal tumors and improved overall survival of laryngeal cancer patients (p = 0.045). Chromatin immunoprecipitation, demethylation experiments, and reporter gene assays revealed that the region of methylation loss can function as a CCAAT/enhancer binding protein alpha (CEBPA)-responsive enhancer element regulating TREX2 expression. CONCLUSIONS: The data highlight a regulatory role of TREX2 DNA methylation for gene expression which might affect incidence and survival of laryngeal cancer. Altered TREX2 protein levels in tumors may affect drug-induced DNA damage repair and provide new tailored therapies.

Long intergenic noncoding RNA 299 methylation in peripheral blood is a biomarker for triple-negative breast cancer.

AIM: To identify DNA methylation biomarkers in peripheral blood samples from triple-negative breast cancer (TNBC) patients. MATERIALS & METHODS: We conducted an epigenome-wide association study (EWAS): the most promising markers were identified in 233 TNBC case-control pairs (discovery set) and subsequently validated in an independent validation set (57 TNBC patients and 124 controls). RESULTS: cg06588802 (LINC00299/ID2) showed a higher methylation in TNBC patients compared with controls (discovery set: 3% increase, p-value = 0.0009; validation set: 2% increase, p-value = 0.01). Consistent results at four neighboring methylation probes and the strong negative correlation (rho = -0.93) with LINC00299 expression add plausibility to this result. CONCLUSION: Hypermethylation of LINC00299 in peripheral blood may constitute a useful circulating biomarker for TNBC.

Changes in A1C levels are significantly associated with changes in levels of the cardiovascular risk biomarker hs-CRP: results from the SteP study.

OBJECTIVE: The effect of therapeutic strategies on cardiovascular (CV) disease can be evaluated by monitoring changes in CV risk biomarkers. This study investigated the effect of a structured self-monitoring of blood glucose (SMBG) protocol and the resulting improvements in glycemic control on changes in high-sensitivity C-reactive protein (hs-CRP) in insulin-naïve patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: The Structured Testing Program (STeP) study was a prospective, cluster-randomized, multicenter trial in which 483 poorly controlled, insulin-naïve patients with type 2 diabetes were randomized to active control (ACG) or structured testing (STG) that included quarterly structured SMBG. Changes in A1C, hs-CRP, and glycemic variability (STG subjects only) were measured at baseline and quarterly. RESULTS: Reductions in geometric mean hs-CRP values were significantly greater in the STG group at months 3 (P = 0.005), 6 (P = 0.0003), and 12 (P = 0.04) than in the ACG group. STG patients at high CV risk (>3 mg/L) showed significantly greater reductions in hs-CRP levels than ACG patients at high CV risk: -3.64 mg/dL (95% CI -4.21 to -3.06) versus -2.18 mg/dL (-2.93 to -1.43), respectively (P = 0.002). There was a strong correlation between reductions in hs-CRP and A1C in both groups: standardized coefficient (ß) was 0.25 for the entire cohort (P < 0.0001), 0.31 for STG (P < 0.0001), and 0.16 for ACG (P = 0.02). CONCLUSIONS: Reductions in hs-CRP level are associated with reductions in A1C but not reductions in lipids or glycemic variability. Comprehensive structured SMBG-based interventions that lower A1C may translate into improvements in CV risk, as evidenced by levels of the biomarker hs-CRP.

Short-term complications of implant-supported and combined tooth-implant-supported fixed dental prostheses.

OBJECTIVE: The objective of this clinical study was to evaluate survival and incidence of complications for metal-ceramic and all-ceramic implant-supported fixed dental prostheses (FDPs) and tooth-implant-supported FDPs. MATERIAL AND METHODS: One-hundred and sixty-six FDPs placed in 132 patients from a prospective study were selected for this retrospective analysis. Included were 91 conventional implant-supported FDPs with implant support on both extremities, 27 implant-supported cantilever FDPs, and 48 tooth-implant-supported FDPs. All restorations were veneered with ceramic. Twenty-six FDPs had a zirconia framework and 140 had a metal framework. Kaplan-Meier analysis was performed to estimate FDP success defined as complication-free survival and the Cox regression model was used to isolate risk factors for the most frequent complications. RESULTS: Within a median follow-up of 1 year and 2 months, three failures were caused by a failed implant (n = 2) and by extended chipping of the veneer (n = 1). In contrast with this low incidence of failure was a high incidence of complications including chipping (n = 29), loss of retention (n = 35), and abutment fractures (n = 2). Multivariate survival analysis revealed a significantly greater incidence of chipping for males and a tendency to increased incidence of chipping for zirconia-based FDPs. The incidence of loss of retention tended to be less for tooth-implant-supported FDPs, for which semi-permanent cement was the only significant risk factor, with a hazard ratio of almost 5. CONCLUSIONS: As chipping of the ceramic veneer was the most frequent complication leading to substantial aftercare, improvements of ceramic veneers are desirable for zirconia-based and metal-based FDPs.

The management of dental anxiety and impact of psychosomatic factors on dentistry: is recent scientific research translated into German dental practices?

This study investigated the dentists' knowledge about psychosomatic medicine. Anxiolytic techniques, considerations about psychosomatic medicine, and referrals to psychotherapists were examined by a questionnaire. Overall, 65 percent felt negatively affected by patients with dental fear. Few dentists used relaxation techniques and hypnosis. The relationship between psychosomatic factors and pain perception was well known, but not their impact on wound healing. The frequency of continuing education courses correlated with a broader range of treatment techniques and less difficulties in treatment. Research evidence about the impact of psychological factors on dental treatment has not been translated into dental practice.

Potential canonical wnt pathway activation in high-grade astrocytomas.

Aberrant wnt pathway activation through cytoplasmic stabilization of ß-catenin is crucial for the development of various human malignancies. In gliomagenesis, the role of canonical (i.e., ß-catenin-dependent) signalling is largely unknown. Here, we studied canonical wnt pathway activation in 15 short-term cultures from high-grade gliomas and potential pathomechanisms leading to cytoplasmic ß-catenin accumulation. Furthermore, we assessed the prognostic relevance of ß-catenin expression in a tissue microarray comprising 283 astrocytomas. Expression of ß-catenin, its transcriptional cofactors TCF-1 and TCF-4 as well as GSK-3ß and APC, constituents of the ß-catenin degradation complex was confirmed by RT-PCR in all cultures. A cytoplasmic ß-catenin pool was detectable in 13/15 cultures leading to some transcriptional activity assessed by luciferase reporter gene assay in 8/13. Unlike other malignancies, characteristic mutations of ß-catenin and APC leading to cytoplasmic stabilization of ß-catenin were excluded by direct sequencing or protein truncation test. In patient tissues, ß-catenin expression was directly and its degradation product's (ß-catenin-P654) expression was inversely correlated with WHO grade. Increased ß-catenin expression and low ß-catenin-P654 expression were associated with shorter survival. Altogether, we report on potential canonical wnt pathway activation in high-grade gliomas and demonstrate that ß-catenin expression in astrocytomas is associated with increased malignancy and adverse outcome.

Familial bladder cancer and the related genes.

PURPOSE OF REVIEW: Family history of bladder cancer is a known risk factor for bladder cancer but new data have emerged on the influence of a family history of other tumours than bladder cancer. Recent data have shown that family history influences survival of bladder cancer. Gene identification has been successful particularly on low-risk genes influencing susceptibility and prognosis. RECENT FINDINGS: Familial clustering of bladder cancer has been found with cancers of the stomach, larynx, kidney, endometrium and the bone marrow (leukaemia). Shared smoking habits are an explanation to these findings and between spouses these appear to be the only explanation to the clustering of cancers with bladder cancer. Family members also share prognosis of bladder cancer, either good or poor survival. Among the low-penetrant genes, the variants within the genes encoding metabolic enzymes have been consistently associated with susceptibility to bladder cancer and the evidence is compelling for NAT2 slow acetylator and GSTM1 null genotypes. SUMMARY: Smoking is the only identifiable environmental factor explaining familial clustering of bladder cancers and other cancers. Genetic factors are likely to contribute to many of the described associations but the identified genes are probably an introduction to the genetics of bladder cancer.

Associated cancers in parents and offspring of polycythaemia vera and myelofibrosis patients.

Polycythaemia vera (PV) and primary myelofibrosis (MF) show concordant familial clustering but limited population level data are available on the aggregation of other discordant neoplasms in these families. We used the Swedish Family-Cancer Database to assess risks for VP and MF in families of cancer patients. A total of 3530 first PV and 1606 MF patients were identified, with high concordant familial risks. Several discordant familial associations were found for PV (acute myeloid leukaemia, Hodgkin disease, prostate and bladder cancers) or for MF (chronic lymphatic leukaemia, colorectal, kidney and cervical cancers) or for both (nervous system, eye and endocrine tumours).

Comparison of measures for haplotype similarity.

Measuring the association of haplotype similarities with phenotype similarities has been used to develop statistical tests of genetic association. Previously, we applied the general approach of Mantel statistics to correlate genetic and phenotype similarity, where genetic similarity was defined by the number of intervals flanked by markers identical by state for pairs of haplotypes. Here we investigated in the case-control study design the effect on power of the Mantel statistics for five different measures of genetic similarity based on haplotypes: 1) the number of shared intervals, 2) the physical length of the shared intervals, 3) the genetic length of the shared intervals in centimorgans, 4) the genetic length of the shared intervals in linkage disequilibrium units (LDU) and 5) Yu's measure that attaches more weight to the sharing of rare than common alleles. With prior knowledge of the answers of Genetic Analysis Workshop 15 Problem 3, we analyzed the simulated data sets in two genomic regions surrounding the disease loci on chromosomes 6 and 18. For the dense map on chromosome 6, all methods showed a very high power of comparable magnitude. For chromosome 18, we observed a power between 19% and 99% at the pointwise 5% significance level using 1000 cases and 1000 controls for all methods except Yu's measure. While it yielded a much lower power, Yu's measure had 80% power around the disease locus.

Association of genetic variants in the Rho guanine nucleotide exchange factor AKAP13 with familial breast cancer.

The A-kinase anchor protein 13 (AKAP13, alias BRX and lbc) tethers cAMP-dependent protein kinase to its subcellular environment and catalyses Rho GTPases activity as a guanine nucleotide exchange factor. The crucial role of members of the Rho family of GTPases in carcinogenesis is well established and targeting Rho proteins with antineoplastic compounds has become a major effort in the fight against cancer. Thus, genetic alterations within the candidate cancer susceptibility gene AKAP13 would be expected to provoke a constitutive Rho signalling, thereby facilitating the development of cancer. Here, we analysed the potential impact of four polymorphic non-conservative amino acid exchanges (Arg494Trp, Lys526Gln, Asn1086Asp and Gly2461Ser) in AKAP13 on familial breast cancer. We performed a case-control study using genomic DNA of BRCA1/2 mutation-negative German female index patients from 601 unrelated families, among a subset of 356 high-risk families, and 1053 German female unrelated controls. The newfound Lys526Gln polymorphism revealed a significant association with familial breast cancer (OR = 1.58, 95% CI = 1.07-2.35) and an even stronger association with high-risk familial breast cancer (OR = 1.85, 95% CI = 1.19-2.88). Haplotype analyses were in line with genotype results displaying a similar significance as analyses of individual polymorphisms. Due to the pivotal role of AKAP13 in the Rho GTPases signalling network, this variant might affect the susceptibility to other cancers as well.

c-MYC Asn11Ser is associated with increased risk for familial breast cancer.

c-MYC is a multifaceted protein that regulates cell proliferation, differentiation and apoptosis. Its crucial role in diverse cancers has been demonstrated in several studies. Here, we analysed the influence of the rare c-MYC Asn11Ser polymorphism on familial breast cancer risk by performing a case-control study with a Polish (cases n = 349; controls n = 441) and a German (cases n = 356; controls n = 655) study population. All cases have been tested negative for mutations in the BRCA1 and BRCA2 genes. A joint analysis of the Polish and the German study population revealed a 54% increased risk for breast cancer associated with the heterozygous Asn11Ser variant (OR = 1.54, 95% CI 1.05-2.26, p = 0.028). The breast cancer risk associated with this genotype increases above the age of 50 years (OR = 2.24, 95% CI 1.20-4.21, p = 0.012). The wild-type amino acid Asn of this polymorphism is located in the N-terminal MYC transactivation domain and is highly conserved not only among most diverse species but also in the N-MYC homologue. Due to the pivotal role of c-MYC in diverse tumours, this variant might affect the genetic susceptibility of other cancers as well.